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Rev. Bras. Cardiol. Invasiva vol.22 número4


Academic year: 2018

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© 2014 Sociedade Brasileira de Hemodinâmica e Cardiologia Intervencionista. Published by Elsevier Editora Ltda. All rights reserved.

Preliminary Report of Serum Nickel

Concentration After Atrial Septal Defect

Occlusion with the Cocoon™ Device

André Vannuchi Badran, Jorge Luis Haddad, Rafael Brolio Pavão, Gustavo Caires Novaes,

Igor Matos Lago, Geraldo Luiz de Figueiredo, Moysés de Oliveira Lima-Filho,

Minna Moreira Dias Romano, J. Antônio Marin-Neto


Background: The possibility of nickel release to the blood-stream after implantation of latest generation atrial septal defect occlusion devices (Cocoon Septal OccluderTM), whose main component is nitinol (55% nickel and 45% titanium), remains controversial, especially in certain groups of patients such as children and women of childbearing age. Thus, the aim of this study was to evaluate the correlation between the device implantation and serum levels of nickel. Methods: This was a prospective longitudinal observational study con-ducted at a public hospital. Patients undergoing percutaneous atrial septal defect occlusion were clinically evaluated using transthoracic echocardiography and peripheral vein blood sampling for serum nickel before and after (1  day, 1 and 3 months) implantation. Results: The procedure and subsequent examinations were successfully performed in ten patients, with mean age of 34.4  years (range 5 to 60  years). Serial echocardiography confirmed the maintenance of adequate results of the procedure. Patients did not show manifesta-tions that might suggest a reaction to metal, such as skin rash, dyspnea, thoracic discomfort, palpitations or migraine. Serum nickel levels did not show any significant changes and remained within the normal range for the population, according to the dosing methods within 3 months of the pro-cedure. Conclusions: Preliminary results of this investigation with the Cocoon device have shown that during the initial period of endothelization after the procedure there was no significant nickel release into the bloodstream.

DESCRIPTORS: Heart septal defects, atrial. Prostheses and implants. Metals. Nickel. Hypersensitivity.

Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Uni-versidade de São Paulo, Ribeirão Preto, SP, Brazil.

Correspondence to: André Vannuchi Badran. Seção de Cardiologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Campus Universitário − Monte Alegre − CEP: 14048-900 – Ribeirão Preto, SP, Brazil

E-mail: andrevbadran@gmail.com

Received on: 10/6/2014 • Accepted on: 11/30/2014

Original Article


Relato Preliminar sobre a Concentração Sanguínea de Níquel Após Oclusão Percutânea de

Comunicação Interatrial com a Prótese Cocoon®

Introdução: A possibilidade de ocorrer liberação de níquel na corrente sanguínea após implante de dispositivos oclusores de comunicação interatrial de última geração (Cocoon Septal Oc-cluder®), cujo principal componente é o nitinol (55% de níquel e 45% de titânio), ainda permanece controversa, principalmente em determinados grupos de pacientes, como crianças e mulheres em idade fértil. Dessa maneira, o objetivo do presente estudo foi avaliar a correlação entre o implante da prótese e os níveis séricos de níquel. Métodos: Estudo prospectivo de coorte, longitudinal e observacional, realizado em um hospital público. Pacientes submetidos à oclusão percutânea de comunicação interatrial foram avaliados clinicamente, por meio de ecocardiograma transtorácico, e foi feita coleta de amostras de sangue em veia periférica, para a dosagem do níquel antes e após (1 dia, 1 e 3 meses) o implante. Resultados: O procedimento e os exames subsequentes foram realizados com sucesso em dez pacientes, com média de idade de 34,4 anos (variação de 5 a 60 anos). O ecocardiograma seriado comprovou a manutenção dos resultados adequados do implante dos dispositivos. Os pacientes não apre-sentaram manifestações que pudessem sugerir reação ao metal, como rash cutâneo, dispneia, desconforto torácico, palpitações ou migrânea. Níveis séricos de níquel não apresentaram variação signiicativa e se mantiveram dentro dos limites de normalidade populacional dos métodos de dosagem até os 3 meses decorridos do procedimento. Conclusões: Os resultados preliminares desta investigação com a prótese Cocoon demonstraram que, durante o período inicial de endotelização após o procedimento, não ocorreu liberação apreciável de níquel para a corrente sanguínea.



he percutaneous closure of atrial septal defect (ASD) is the subject of constant research and de-velopment. Since it was irst described in 1974,1 as

well as since the irst Brazilian publication, in 1996,2

double-disc stainless steel prostheses have predominated. The discs of these early models, which did not have a centralization mechanism, were one of the causes of their disuse, due to the dificult repositioning and handling of the prostheses.3

Most currently used devices consists of a nickel (55%) and titanium (45%) alloy,4 also known as nitinol

(Nickel TItanium Naval Ordnance Laboratory), developed in the 1960s by the United States Navy.5 Nitinol has

favorable physicochemical properties such as resistance to corrosion and material fatigue, thermal memory, and elasticity, which allow for the passage of large devices through small catheters, in addition to non-ferrous properties, which even allow the performance of MRI after implantation.4,5

Considered a safe and effective alternative to con-ventional surgical atrioseptoplasty,4,6,7 such implants face

new questions in the follow-up of a technique that has been under development for almost 40 years.

The main component of these prostheses, i.e., nickel, may be detectable in the bloodstream at higher levels than usual, which brings relevant implications regarding their biocompatibility.8 This is a non-existent problem in

regard to stainless steel devices, which after implantation manifest a protective neointimal ibrous capsule that is up to 2  mm thick. Nitinol, in turn, produces a thinner neointimal response, which may be correlated to the oxidation of its supericial layer and the consequent release of metal ions into the bloodstream,5 which are

therefore responsible for a higher serum concentration than that found in the general population. The latter, in theory, would be exposed to lower levels of nickel, introduced by water and food, and also through other routes, such as inhalation and even hemodialysis.9,10 In

occupational exposure, there is inhalation of metallic dust and fumes containing relatively insoluble nickel compounds (nickel particulates), aerosols derived from nickel solutions, or gaseous forms (such as carbonyl nickel, for instance). The water-soluble forms are more easily absorbed, whereas the metallic form is the least absorbed.11

Allergy after nitinol prosthesis implantation has been rarely described, with the development of skin rash,12 as well as other symptoms such as dyspnea,

pericarditis, chest discomfort, palpitations, and mi-graine with or without aura.3,4,13,14 These symptoms

were more frequent in individuals that had a positive skin test reaction to nickel.15 More alarmingly, there

are cases reports in which it was decided to explants the prosthesis without accurate or proven definition of the allergic reaction.14 The occurrences, although

rare, tend to manifest from 24 hours up to 6  weeks after device implantation.4

It is suspected that the severity of allergic reac-tions to nickel is directly proportional to the amount of nickel released into the bloodstream. In a randomized, double-blinded, placebo-controlled trial, in which a nickel solution was offered orally, it was documented that in the case of individuals who had previously shown nickel sensitization in skin tests, the longer the exposure, the higher the degree of skin manifestation.16

In a prospective study of 67  patients submitted to im-plantation of AmplatzerTM Septal Occluder devices (AGA

Medical Corporation, Golden Valley, United States), an increase in serum nickel levels was documented, which reached its peak in the irst month, without the occurrence of allergic manifestations.8

Multiple factors could inluence the occurrence of clinical manifestations after prosthesis implantation, including nickel mass, the prosthesis surface exposed to the bloodstream, and the quality of nitinol wire used.15

In this context, latest-generation prostheses used to oc-clude atrial septal defects have been developed with coated nitinol wires.3,15 Therefore, they might present a

distinct pattern of nickel release into the bloodstream. The present study, which is preliminary and pioneering, aimed to study this fact.


Study design

This was a prospective cohort, longitudinal, ob-servational study, performed at a single center, from August of 2013 to October of 2014, including 10 pro-cedures from a total number of 20 patients undergo-ing percutaneous ASD occlusion usundergo-ing Cocoon Septal OccluderTM (Vascular Innovations Co. Ltd., Bangtanai,

Thailand) prostheses. The study was performed at the Interventional Cardiology Laboratory of Hospital de Ribeirão Preto Medical School, Universidade de São Paulo, and was approved by the Research Ethics Com-mittee of the institution (Opinion 174.986). All patients or their legal guardians, in case of underage patients, signed an informed consent after being notiied of the study purposes.

Inclusion criteria


Exclusion Criteria

The exclusion criteria were: (1) a history of hy-persensitivity or occupational exposure to nickel; (2) other congenital or acquired heart diseases, which had formal indication for surgical repair, as well as thin, hypermobile, or deicient septal defect edges; (3) ac-tive infection of any kind or infectious process in the previous month; or (4) hypercoagulability syndrome or contraindication to antiplatelet drugs.

One patient was withdrawn from the study, a pros-thesis embolization into the left ventricle was observed approximately 24  hours after implantation, which re-quired surgery to remove the device and ASD closure.


This study assessed nickel release correlated with the implantation of the latest-generation atrial septal defect occlusion devices by serial nickel measurements in serum. The Cocoon Septal OccluderTM prostheses

are manufactured using platinum-coated nitinol wire through a nano-fusion process. This characteristic could, in theory, result in a different behavior when compared to other devices previously submitted to similar assessment.


All ten patients were clinically evaluated through transthoracic echocardiography and collection of periph-eral blood samples for nickel measurement before and after (1 day; 1 and 3 months) the implant, with protocol intention to repeat the measurement 6 months and one year after the implant. During the study, due to labora-tory methodological reasons, the nickel measurement technique using atomic absorption spectrophotometry – graphite furnace – (normal <  4  mcg/L) was replaced

by mass spectrometry with inductively coupled plasma (normal < 7.5 mcg/L), which is more sensitive and can detect lower serum nickel levels with greater accuracy.17

During follow-up, patients were medically treated with acetylsalicylic acid at a single daily dose of 5 mg/kg (maximum dose of 100 mg/day) for 6 months. In adult patients, clopidogrel was associated at a dose of 75 mg/ day for 3  months, with the intention to maintain it up to 6  months. Antibacterial prophylaxis was prescribed in case of surgical or interventional procedures, during the irst 6  months of follow-up.

Statistical Analysis

Continuous variables were described with maximum and minimum values as well as means and standard deviations. Categorical variables were described as frequencies or percentages.


A total of ten patients, of whom six were women, were successfully submitted to the procedure. Age ranged from 5 to 60 years, with a mean of 34.4 years. Patient follow-up was 3 to 15  months (Table 1).

The implant was possible in all patients. Two patients had residual shunt at the transthoracic echocardiogram performed on the following day. After 30 days, minimal residual low was observed in only one patient.

The patients had no clinical signs or manifestations that would suggest reaction to metal, such as skin rash, dyspnea, chest discomfort, palpitations, or migraine.

Measurement of the serum levels, due to the use of two different laboratory methods, is shown in absolute values (Table 2), as well as the ratio between nickel mea-surement/upper limit of the method’s normality (Figure).


Demographic, hemodynamic, and technical aspects of the atrial septal defect (ASD) occlusion procedure

Patients Age (years) Weight (kg) Gender ASD diameter (mm) QP/QS

Prosthesis (mm)

Immediate residual flow

Residual flow after 30 days

1 49 100 M 31 NA 36 No No

2 51 63 F 19 2.3 24 No No

3 5 25 F 12 NA 14 No No

4 60 55 F 20 NA 24 No No

5 45 59.3 F 8 1.94 12 No No

6 18 67 M 11 NA 14 No No

7 35 50 F 14 NA 16 No No

8 54 93 F 26 NA 32 Mild Mild

9 12 57 M 16 NA 18 Mild No

10 15 65 M 14 NA 16 No No



The development of nitinol has yielded undeniable progress, not only in cardiology but also in the incor-poration to surgical resources in several procedures. Although its main component, nickel, is an essential element for nutrition in humans, implant devices that contain this metal deserve attention due totheirtoxic,8,11,18

allergic,9,15,18 and perhaps oncogenic and


Once the bloodstream is reached, 75%11 of plasma

nickel is carried by the circulating proteins, such as albumin and alpha-2 macroglobulin (called “nickel plasmin”). As the Ni2+ ions do not have a speciic

mechanism of uptake, they probably enter cells by Ca2+/Mg2+ channels. The main nickel elimination route

is urinary, with the urinary excretion half-life ranging from 4.6 to 23  hours.11 The measurement of urinary

nickel levels is a currently used as a parameter of oc-cupational safety control in some countries, but not by the national legislation. The regulatory standards that legislate and provide guidance on mandatory procedures

related to safety and occupational medicine, which are periodically reviewed by the Brazilian Ministry of Labor and Employment, included, in their 1978 version,11

the reference values for the maximum allowed urinary nickel levels. In the latest version, from1994,11 there is

no reference to the acceptable levels of urinary nickel. Some of the adverse effects caused by the nickel occur due to its capacity to substitute essential ele-ments such as manganese and to promote a possible effect of prolactin release.18 An in vitro genotoxic effect

thas also been described, acting in the S phase of the cell cycle, when there is heterochromatic DNA replication;18 however, there are conflicting data in

vivo, in an attempt to define it as a carcinogenic or

teratogenic factor, both in exposed workers and in experimental models.9,18

The most important and prevalent health effects resulting from exposure to nickel is the allergic mani-festation.9,15,18 A type IV hypersensitivity reaction (Gell

and Coombs) develops, mainly caused by prolonged and repeated skin exposure to items such as clothing accessories (zippers, buttons, and decorations), clips, razor blades, cell phones, etc. It has a prevalence of 8-15%13,19 in the general population, which is even

more pronounced in women – up to 17%.12 Due to the

higher prevalence of ASD in women, with proportions close to 2:1,20 this population would be more often

subject to exposure. Despite this fact, nickel exposure response through non-skin implants, as in ASD, still shows some uncertainties. For instance, studies have shown inlammatory activity with T-lymphocytes in peri-orthopedic implants in the hip of patients with a history of hypersensitivity skin reaction to metal, while other studies have shown conlicting results.19

A technological experimental study evaluated the behavior of 240 AmplatzerTM prostheses submitted to

resistance testing with 400 million cycles, soaked in saline solution at 37°C for 14 months. After this period, the prostheses were evaluated through electron micros-copy. There were no signs of microfracturesor corro-sion in the nitinol structures.5 This demonstrates that,

regarding this model, the prosthesis has a low nickel release potential, even when submitted to extended wear under experimental conditions.5

In another study, which also used the AmplatzerTM

prostheses, serum nickel levels were evaluated by atomic absorption spectrophotometry in 67 patients with ASD or patent foramen ovale (PFO).8 Blood samples were

collected before and after implantation (1  day; 3 and 12  months). The following values were obtained, re-spectively, in ng/mL: 0.47; 1.27; 1.5; 1.24, and 0.25. These results suggest a transient increase, especially in the third month after implantation.8

In addition to the potential adverse effects discussed above, the possibility has been considered that, while the nickel serum levels were elevated, there was no

Figure – Means by period of association between nickel measurement and the method’supper limit of normality.


Serum nickel levels (mcg/L)

Pre-implantation 1 Day 1 Month 3 Months

A: < 2 A < 2 B: 3.9 B: 7.6

A: 0.82 A: 1.04 Not collected Not collected

A: 3.2 A: 3.1 A: 3.9 A: < 2

Hemolysis Hemolysis A: 1.9 A: 2.5

A: 2.4 A: 2.6 A: 1.3 A: < 2

B: 8.1 B: 6 B: 1.8 B: 0.8

B: 2.7 B: 3.4 B: 0.5 B: 1.3

B: 3.9 B: 4.1 B: 1 B: 1.8

B: 3.6 B: 4.6 B: 0.6 B: 0.8

A: atomic absorption spectrophotometry: normal < 4 mcg/L; B: mass spectrometry with inductively coupled plasma: normal < 7.5 mcg/L. In bold: slightly exceeding the upper limit of normality.

Pre-implantation 1 Day 1 Month 3 Months 0.6







complete endothelial coverage of the device. Therefore, it would be plausible to maintain antiplatelet therapy while there is no normalization of serum nickel levels, which usually occurs within a period of 3 to 12 months.21

A histological study in ten nitinol devices, which had to be explanted from patients for several reasons, such as inadequate positioning or signiicant residual shunt in a period ranging from 5  days to 48  months after implantation, contributed to the understanding of so-called neoendothelization at the prosthesis implanta-tion site.22 At the assessment by light microscopy and

immunohistochemical panel, it was observed that the cell organization process initially forms ibrin deposits within a period of 5 days to 2 months and, subsequently, the differentiation occurs in cells with endothelial im-munohistochemical characteristics. The endothelization would be complete 24 months after the implantation.22

Considering the results of this investigation, in which there was no increase in serum concentrations of nickel, it can be inferred that the nitinol strut coating prevented its release into the bloodstream. It could also be a sign of early endothelization, according to the experimental studies,5,8 a fact that would induce a shorter time of use

of antiplatelet agents and antibacterial prophylaxis in the absence of residual shunt.

In the present sample, basal nickel values observed before the prosthesis implantation were higher than those found in literature.8 Considering this result, it

is important to consider some factors. Regarding the laboratory method, atomic absorption spectrophotom-etry, it is known that this method is affected by several pathological conditions, such as myocardial infarction.23

The assessment, at necropsies, of human myocardial tissues of previously healthy individuals that died from accidental causes has demonstrated that the heart is the preferred site of higher nickel deposition, when com-pared to other tissues.23 It has been considered possible

that the concomitant increase in albumin and nickel plasmin after the infarction could justify higher nickel concentrations. Other situations can also alter its serum levels, such as fractures, stroke, and burns.23

Addition-ally, there may be aspects related to diet, including nickel-rich foods such as cocoa, cereals, and grains.11

In the present study, it is noteworthy that serum alterations observed in nickel blood levels showed no direct correlation with the time of implantation. Thus, given the possibility that these results relect luctua-tions explained by the small sample size, the authors intend to pursue the inclusion of patients in this study, as well as to complete the follow-up with additional collections for up to one year of prosthesis implantation.

In agreement with a recent publication by Chamié et al.3 regarding the two new coated nitinol mesh

prostheses, about which there are few references in the literature and that have been implanted in 49 patients (Lifetech CERATM ASD Occluder and Cocoon

Septal OccluderTM), it was observed that the handling

and the functional proile of the devices used are very satisfactory. More studies and a long-term follow-up are needed to document some aspects related to the potential beneits of coated nitinol wires, which in ad-dition to increasing the device radiopacity, facilitating its visualization and its positioning under luoroscopy, appear, considering the results of this investigation, to promote the effects of reduced nickel release into the bloodstream and increased occluder biocompatibility.3 CONCLUSIONS

The preliminary results of this investigation with the CocoonTM prosthesis showed that, during the initial

period of endothelization after the procedure, there was no signiicant release of nickel into the bloodstream.


The authors declare no conlicts of interest.


None declared.


The Cocoon Septal OccluderTM (Vascular Innovations

Co. Ltd., Bangtanai, Thailand) prostheses used in the study were donated to Hospital das Clínicas de Ribeirão Preto Medical School, Universidade de São Paulo by its importer and representative in Brazil, ArtMedica Ltda.

The measurement of blood nickel levels were per-formed by Laboratório Baracchini de Análises Clínicas, in Ribeirão Preto (SP).


1. King TD, Mills NL. Nonoperative closure of atrial septal defects. Surgery. 1974;75(3):383-8.

2. Haddad JL, Secches A, Finzi L, Kajita L, Constantini C, Sideris E, et al. Oclusão percutânea transvenosa de comunicação interatrial mediante utilização do Buttoned Device. Arq Bras Cardiol. 1996;67(1):17-22.

3. Chamié F, Chamié D, Simões LCN, Mattos R. Oclusão per-cutânea das comunicações interatriais tipo ostium secundum com próteses de nitinol revestidas de última geração. Rev Bras Cardiol Invasiva. 2014;22(1):41-7.

4. Ansari HZ, Sadanandan H. Allergic reaction to percutaneously placed amplatzer device for symptomatic patent foramen ovale. J Clin Case Rep. 2013;3:324.

5. Kong H, Wilkinson JL, Coe JY, Gu X, Urness M, Kim T, et al. Corrosive behaviour of Amplatzer® devices in experimental and biological environments. Cardiol Young. 2002;12(2): 260-5.

6. Haddad JL, Novaes GC, Pavão RB, Badran AV, Lemos DC, Lago IM, et al. Oclusão percutânea de comunicação interatrial tipo ostium secundum com prótese memopart. Rev Bras Cardiol Invasiva. 2013;21(4):2-7.


8. Ries MW, Kampmann C, Rupprecht H, Hintereder G, Hafner G, Meyer J. Nickel release after implantation of the Amplatzer occluder. Am Heart J. 2003;145(4):737-41.

9. Young RA. Formal toxicity summary for nickel and nickel compounds [Internet]. Oak Ridge: Oak Ridge National Labo-ratory; 1995 [cited 2014 Oct 15]. Available from: http://rais. ornl.gov/tox/proiles/nickel_and_nickel_compounds_f_V1.html 10. Tonelli M, Wiebe N, Hemmelgarn B, Klarenbach S, Field C,

Manns B, et al. Trace elements in hemodialysis patients: a systematic review and meta-analysis. BMC Med. 2009;7:25. 11. Santos CR. Avaliação dos indicadores biológicos de exposição

aos metais em trabalhadores de fundições [tese doutorado]. Ribeirão Preto: Faculdade de Ciências Farmacêuticas, Univer-sidade de São Paulo; 2004.

12. Basko-Plluska JL, Thyssen JP, Schalock PC. Cutaneous and systemic hypersensitivity reactions to metallic implants. Der-matitis.2011;22(2):65-79.

13. Wertman B, Azarbal B, Riedl M, Tobis J. Adverse events associ-ated with nickel allergy in patients undergoing percutaneous atrial septal defect or patent foramen ovale closure. Research correspondence. J Am Coll Cardiol. 2006;47(6):1226-38. 14. Belohlavek J, Belohlavkova S, Hlubocky J, Mrazek V, Linhart

A, Podzimek S. Severe allergic dermatitis after closure of foramen ovale with Amplatzer occluder. Ann Thorac Surg. 2013;96(3):e57-9.

15. Dasika UK, Kanter KR, Vincent R. Nickel allergy to the percuta-neous patent foramen ovale occluder and subsequent systemic nickel allergy. J Thorac Cardiovasc Surg. 2003;126(6):2112. 16. Jensen CS, Menne T, Libsy S, Kristiansen J, Veien NK.

Experi-mental systemic contact dermatitis from nickel: a dose-response study. Contact Dermatitis. 2003;49(3):124-32.

17. Nunes JA. Desenvolvimento de método para determina-ção de Ag, As, Cd, Co, Mn, Ni, Pb e Se em sangue por espectrometria de massas com fonte de plasma acoplado indutivamente (ICP-MS) [dissertação mestrado]. Ribeirão Preto: Faculdade de Ciências Farmacêuticas, Universidade de São Paulo; 2009.

18. U.S. Department of Health and Human Services; Public Health Services, Agency for Toxic Substances and Disease Registry. Toxicological proile for lead [Internet]. Atlanta: ATSDR; 2005 [cited 2014 Oct 15]. Available from: http://www.atsdr.cdc. gov/ toxproiles/tp13.pdf

19. Romero-Brufau S, Best PJM, Holmes Jr DR, Mathew V, Da-vis MDP, Sandhu GS, et al. Outcomes after coronary stent implantation in patients with metal allergy. Circ Cardiovasc Interv.2012;5(2):220-6.

20. Maciel BC, Marin Neto JA. Manual de condutas clínicas cardiológicas. São Paulo: Segmento Farma; 2005.

21. Burian M, Neuman T, Weber M, Brandt R, Geisslinger G, Mitrovic V, et al. Nickel release, a possible indicator for the duration of antiplatelet treatment, from a nickel cardiac device in vivo: a study in patiets with atrial septal defects implanted with an Amplatzer occluder. Int J Pharmacol Ther. 2006;44(3):107-12.

22. Foth R, Quentin T, Michel-Behnke I, Vogt M, Kriebel T, Kreischer A, et al. Immunohistochemical characterization of neotissues and tissue reactions to septal defect occlusion devices. Circ Cardiovasc Interv. 2009;2(2):90-6.


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